Marijuana is the most frequently abused illegal drug in the U.S., particularly among young people. The widespread abuse of marijuana continues despite the clear documentation that this is associated with adverse effects. This R21 proposal is driven by our desire to conduct coordinated PET and neuropsychological studies of the relationships between the kinetics of entry into and initial clearance from the brain of (-)-delta-9-tetrahydrocannabinol (THC), the major active ingredient of cannabis smoke, and the subjective and physiological effects of this drug in individual human subjects. We hypothesize that, as with other abused substances, its rewarding potency depends on the rate of entry into4cthe brain. These studies require the labeling of THC with carbon-I I, a nuclide with half-life of 20 minutes, whose concentration can be measured in the human body using positron emission tomography. Our group has extensive experience in the synthesis of novel positron emitting tracers including many carbon-I I labeled compounds and a fluorine-18 labeled analog of delta-8 THC (a biologically active isomer of delta-9-THC that is a minor constituent of cannabis). Our prior studies also include the synthesis and biological evaluation of several agonist and antagonist radioligands that bind to the brain cannabinoid (CBI) receptor in vivo. However, the rapid synthesis of carbon-I I labeled delta-9-THC presents some technical challenges that are expected to require approximately two years to solve, and trial of several approaches that are detailed in this proposal. It should be noted that, based on our experience with several CBI receptor radioligands of higher affinity and lower lipophilicity than THC, we do not expect that carbon-I I labeled delta-9-THC will have good properties for imaging the distribution of this receptor. Rather, the purpose of preparing carbon-I I labeled delta-9- is to study the regional brain pharmacokinetics of this drug after intravenous administration to human subjects.